Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Clin Exp Med. 2024 Sep 12;24(1):219. doi: 10.1007/s10238-024-01479-w.
Resistance to immunotherapy poses a significant challenge in the treatment of colorectal cancer (CRC), and the underlying mechanisms are not fully understood. Recent studies have implicated PFKFB3, a crucial glycolytic enzyme, in shaping the tumor microenvironment in CRC. Our study aimed to systematically study the role of PFKFB3 in CRC. Bioinformatic analysis revealed that PFKFB3 expression is notably elevated in CRC tissues compared to normal counterparts. In vivo experiments confirmed that suppressing PFKFB3 reduces the tumorigenesis of CRC. We identified multiple cancer-associated pathways positively correlated with high expression of PFKFB3, such as epithelial-mesenchymal transition (EMT), hypoxia, KRAS signaling, angiogenesis, PI3K/AKT/mTOR, Hedgehog, and Notch pathways. Additionally, PFKFB3 exhibited significant correlations with various immune-related pathways, including complement, IL-2/STAT5, IL-6/JAK/STAT3, IFN-α/IFN-γ, TGF-β, and TNF-α/NF-κB, as well as several immunosuppressive cell markers found in regulatory T cells (CCR8, TGFB1, STAT5B, FOXP3), M2 macrophages (CD163, VSIG4, MS4A4A), T cell exhaustion markers (CTLA-4, PDCD1, LAG3), and PD-L1. Intriguingly, increased PFKFB3 expression was observed in PD-L1 blockade-resistant patients and was associated with shorter overall survival. In a nutshell, PFKFB3 plays an important role in CRC tumorigenesis and resistance to immunotherapy. Targeting PFKFB3 inhibits tumor formation and enhances the efficacy of immunotherapy. Our findings underscore the functions of PFKFB3 in CRC, shedding light on both cancer-related and immunosuppressive pathways.
免疫疗法耐药性是结直肠癌（CRC）治疗中的一个重大挑战，其潜在机制尚未完全阐明。最近的研究表明，PFKFB3 是一种关键的糖酵解酶，参与了 CRC 肿瘤微环境的形成。我们的研究旨在系统研究 PFKFB3 在 CRC 中的作用。生物信息学分析显示，PFKFB3 在 CRC 组织中的表达明显高于正常组织。体内实验证实，抑制 PFKFB3 可降低 CRC 的肿瘤发生。我们确定了多个与 PFKFB3 高表达呈正相关的癌症相关途径，如上皮间质转化（EMT）、缺氧、KRAS 信号、血管生成、PI3K/AKT/mTOR、Hedgehog 和 Notch 途径。此外，PFKFB3 与多种免疫相关途径显著相关，包括补体、IL-2/STAT5、IL-6/JAK/STAT3、IFN-α/IFN-γ、TGF-β和 TNF-α/NF-κB，以及调节性 T 细胞（CCR8、TGFB1、STAT5B、FOXP3）、M2 巨噬细胞（CD163、VSIG4、MS4A4A）、T 细胞耗竭标志物（CTLA-4、PDCD1、LAG3）和 PD-L1 中的几种免疫抑制细胞标志物。有趣的是，在 PD-L1 阻断耐药患者中观察到 PFKFB3 表达增加，并且与总生存期缩短相关。总之，PFKFB3 在 CRC 肿瘤发生和免疫治疗耐药中发挥重要作用。靶向 PFKFB3 可抑制肿瘤形成并增强免疫治疗的疗效。我们的研究结果强调了 PFKFB3 在 CRC 中的作用，揭示了与癌症相关和免疫抑制途径相关的功能。
